{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE307nnn/GSE307192/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Mus musculus"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE307192"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Effector CD4 T cells convert transient responses to KRAS targeted therapy into long term durable remissions in pancreatic cancer","description":"Pancreatic ductal adenocarcinoma (PDAC) is refractory to most therapies, including immunotherapies where reinvigoration of CD8 T cells is insufficient to induce long-term durable remissions. Direct inhibitors of KRAS are clinically promising although acquired resistance is common. Interleukin-21 is a plieotropic cytokine with potential to augment anti-tumor immunity. Using AI-assisted computational design, we developed a de novo IL-21 mimic, 21h10, which displays augmented stability and high signaling potency in both humans and mice. We modeled KRAS inhibitor response and relapse in mice with orthotopic PDAC and show that - unlike chemotherapy or checkpoint blockade combinations - combination of 21h10 with KRASi is curative. Efficacy of 21h10 in PDAC is not dependent on CD8 T cells or MHC class I expression by the tumor. Single cell transcriptional profiling with TCRseq reveals oligoclonal expansion of effector Th1 polarized CD4 T cells and loss of Tregs. We show that cDC2-primed, tumor-specific CD4 T cells produce IFNg that acts on macrophages to clear tumor cells. CD4 T cells from blood of patients with PDAC respond robustly to 21h10. Similarly, short-term ex vivo culture of 21h10 with human PDAC induces IFNg production from infiltrating T cells. Thus IL-21-elicited CD4 T cells exert anti-tumor activity in mice and potentially in humans which can convert transient responses to KRAS inhibition to durable remissions.","dates":{"publication":"2026/09/22"},"accession":"GSE307192","cross_references":{"GSM":["GSM9218671","GSM9218660","GSM9218670","GSM9218659","GSM9218669","GSM9218664","GSM9218675","GSM9218674","GSM9218663","GSM9218673","GSM9218662","GSM9218661","GSM9218672","GSM9218668","GSM9218667","GSM9218666","GSM9218676","GSM9218665"],"GPL":["24247"],"GSE":["307192"],"taxon":["Mus musculus"]}}